This proposal is focused on understanding how two clinically relevant drugs, memantine and ketamine, act individually on the same target under physiological conditions. Memantine is approved for the treatment of Alzheimer's disease and has shown promise in treatment of other neurodegenerative diseases, whereas ketamine has shown promise as a rapid antidepressant and as a treatment for neuropathic pain. Although memantine is well tolerated by patients, ketamine causes side effects that resemble the symptoms of schizophrenia. Memantine and ketamine bind to and inhibit N-methyl-D-aspartate receptors (NMDARs). NMDARs are brain proteins that are activated by the neurotransmitter glutamate and are involved in communication between neurons. NMDARs are responsible for learning, memory formation, and other higher order cognitive functions. NMDAR dysfunction is implicated in the development and progression of depression, neuropathic pain, schizophrenia, and neurodegenerative diseases, including Alzheimer's disease. The overall goal of this proposal is to further our understanding, at both the receptor and cellular level, of how memantine and ketamine actions differ under physiological conditions such as during synaptic activity, in the presence of saturating or non-saturating glutamate, and in the presence of a physiological concentration of Mg2+. The long- term goals of this proposal are to better understand NMDAR antagonism under physiological conditions in order to identify features of beneficial drug actions and to incorporate models of open channel blockers into circuit models of neurodegenerative and neuropsychiatric illnesses. Electrophysiological recordings from cells modified to express NMDARs will be used to assess memantine and ketamine action on subtypes of NMDARs. Results from these experiments will be incorporated into quantitative kinetic models of NMDAR inhibition by memantine and ketamine. We will then validate our models with electrophysiological recordings from neurons in brain slices from mice. Our models will aid in the understanding of mechanistic differences between memantine and ketamine action on NMDARs. Findings from this proposal will have broad translational potential and deepen our understanding of NMDAR antagonism.